Chronic Heart FailurePhase 3IRONOUTNCT02188784
Oral Iron Repletion Effects On Oxygen Uptake in Heart Failure
A Phase 3 study testing Polysaccharide Iron Complex 150 mg in people with Chronic Heart Failure, run by Adrian Hernandez at 17 sites in United States.
Trial summary
The purpose of this study is to determine if oral iron (Fe) polysaccharide is superior to oral placebo in improving functional capacity as measured by change in peak VO2 (oxygen uptake) by CPET (Cardiopulmonary Exercise Testing) , of a broad population of patients with HFrEF (Heart Failure with Reduced Ejection… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Heart Failure
- What is being tested?
- Polysaccharide Iron Complex 150 mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 225 participants
- Where
- 17 sitesUnited States
- Study dates
- 3 Sep 2014to 6 Apr 2016
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age >18 years
- Previous clinical diagnosis of heart failure with current New York Heart Association (NYHA) Class II-IV symptoms LVEF≤0.40 within 2 years prior to consent, and ≥3 months after a major change in cardiac status (i.e. CABG or CRT).
- Serum ferritin between 15-100 ng/ml or serum ferritin between 100-299 ng/ml with transferrin saturation <20%
- Hemoglobin 9.0-13.5 g/dL (males), 9-13.5 (females) at time of enrollment
- Stable evidence-based medical therapy for HF (including beta-blocker and ACE-inhibitor/ARB unless previously deemed intolerant, and diuretics as necessary) with </= 100% change in dose for 30 days prior to randomization
- Changes in diuretic dose guided by a patient-directed flexible dosing program are considered stable medical therapy
- Willingness to provide informed consent
Who cannot join
- Presence of a neuromuscular, orthopedic or other non-cardiac condition that prevents the patient from exercise testing on a bicycle/treadmill ergometer and/or inability to achieve an RER ≥ 1.0 on screening/baseline CPET
- Severe renal dysfunction (eGFR< 20 ml/min/1.73m2)
- Severe liver disease (ALT or AST > 3x normal, alkaline phosphatase or bilirubin >2x normal)
- Gastrointestinal conditions known to impair Fe absorption (i.e. inflammatory bowel disease)
- Known active infection as defined by current use of oral or intravenous antimicrobial agents
- Documented active gastrointestinal bleeding
Show all 15Show fewer
- Active malignancy other than non-melanoma skin cancers
- Anemia with known cause other than Fe deficiency or chronic disease
- Fe overload disorders (i.e. hemochromatosis or hemosiderosis)
- History of erythropoietin, IV or oral Fe therapy, or blood transfusion in previous 3 months.
- Current ventricular assist device
- Anticipated cardiac transplantation within the next 4 months
- Primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy, acute myocarditis, constrictive pericarditis or tamponade
- Previous adverse reaction to study drug or other oral Fe preparation
- Known or anticipated pregnancy in the next 4 months
Trial locations and contacts
17 sites in 1 country.
17 sites in 1 country
United States17 sites
Emory University School of Medicine
Atlanta, Georgia, 30322
Johns Hopkins Hospital
Baltimore, Maryland, 21287
Tufts Medical Center
Boston, Massachusetts, 02111
Massachusetts General Hospital
Boston, Massachusetts, 02114
Brigham and Women's Hospital
Boston, Massachusetts, 02115
The University of Vermont - Fletcher Allen Health Care
Burlington, Vermont, 05401
University Hospitals-Case Medical Center
Cleveland, Ohio, 44106
Metor Health System
Cleveland, Ohio, 44109
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
Duke University Medical Center
Durham, North Carolina, 27705
Lancaster General Hospital
Lancaster, Pennsylvania, 17603
University of Utah Hospitals and Clinics
Murray, Utah, 84107
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Thomas Jefferson University
Philadelphia, Pennsylvania, 19107
Mayo Clinic
Rochester, Minnesota, 55905
Saint Louis University Hospital
St Louis, Missouri, 63110
Washington University School of Medicine
St Louis, Missouri, 63110
About this study
The purpose of this study is to determine if oral iron (Fe) polysaccharide is superior to oral placebo in improving functional capacity as measured by change in peak VO2 (oxygen uptake) by CPET (Cardiopulmonary Exercise Testing) , of a broad population of patients with HFrEF (Heart Failure with Reduced Ejection Fraction) and Fe deficiency at 16 weeks.
Hypothesis: In a broad population of HFrEF patients with Fe deficiency, compared to oral placebo, therapy with oral Fe polysaccharide will be associated with improvement in functional capacity at 16 weeks as assessed by CPET.
Read the detailed description
Therapeutic options to further improve functional capacity and symptoms in HF beyond neurohormonal antagonism are limited. Studies have demonstrated impaired oxidative capacity of skeletal muscle among HF patients, which may contribute to symptoms of breathlessness and persistent fatigue.
In addition to its role in erythropoiesis, iron (Fe) plays a critical role in skeletal muscle's oxygen (O2)-storage capacity (myoglobin) and systemic aerobic energy production. As Fe deficiency is common in patients with symptomatic HF, repletion of iron stores may improve submaximal exercise capacity among these patients beyond the effects on erythropoiesis.
While intravenous Fe repletion in HF patients with mild Fe-deficiency (i.e. Ferritin <100 or Ferritin 100-299 with transferrin saturation <20%) with or without anemia global well-being and functional status, oral Fe repletion has not been studied. Furthermore, the efficacy of oral Fe to replete iron stores in a similar population and its impact on functional capacity, measured objectively by peak VO2, remains unknown.
- Conditions
- Chronic Heart Failure
- Being tested
- Polysaccharide Iron Complex 150 mg, Placebo (for Polysaccharide Iron Complex)
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Polysaccharide Iron Complex 150 mgDrug
Also called Feramax 150 mg
Oral Iron
Placebo (for Polysaccharide Iron Complex)Drug
Sugar capsule designed to mimic Polysaccharide Iron Complex.
| Study group | Role | What they receive |
|---|---|---|
| Polysaccharide iron complex 150 mg | Active comparator | oral Fe polysaccharide 150mg twice daily for 16 weeks Receives: Drug: Polysaccharide Iron Complex 150 mg |
| Placebo (for Polysaccharide Iron Complex 150 mg) | Placebo comparator | Oral placebo twice a day for 16 weeks Receives: Drug: Placebo (for Polysaccharide Iron Complex) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Peak VO2 (ml/Min) (VO2 =Oxygen Consumption)
To determine if oral Fe (Iron) polysaccharide is superior to oral placebo in improving functional capacity as measured by change in peak VO2 by CPET (Cardiopulmonary Exercise Testing) , of a broad population of patients with HFrEF (Heart Failure with Reduced Ejection Fraction) and Fe deficiency at 16 weeks.
Measured: Baseline (BL) and Week 16
Secondary outcomes (5)
Change From Baseline in Sub-maximal Exercise Capacity as Assessed by the 6 Minute Walk Test (6MWT)
To determine the impact of oral Fe repletion on Submaximal exercise capacity as measured by 6MWT
Measured: Measured at BL, week 8 and week 16
Change in Plasma NT-pro BNP
To determine the impact of oral Fe repletion on Plasma N-terminal pro-B-type natriuretic peptide (NT-pro BNP)
Measured: Measured at Baseline and Week 16
Change in Health Status: Kansas City Cardiomyopathy Questionnaire (KCCQ) - Clinical Summary Score
To determine the impact of oral Fe repletion on Health Status: KCCQ.
KCCQ is a 23-item, self administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life for patients with congestive heart failure. It is a predictive tool that tracks how patients are doing if they have weakened heart muscle due to prior heart attacks, heart valve problems, viral infections, or other causes.
The KCCQs questions are used to calculate scores in ten domains. Physical Limitation, Symptom Stability, Frequency, Burden and Total Symptom. Social Limitation, Self-Efficacy, Quality of Life, and Clinical Summary. Overall summary: a combined measure of all the above.
For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.
Measured: Measured at Baseline, Week 8 and Week 16
Change From Baseline in O2 Uptake Kinetics as Assessed by Mean Response Time From CPET
To determine the impact of oral Fe repletion on O2 Uptake Kinetics as measured by CPET
Measured: Measured at BL week 16
Change From Baseline in Ventilatory Efficiency Defined by Ve/VCO2
Change from baseline in Ventilatory Efficiency defined by Ve/VCO2 (carbon dioxide output) as measured by CPET
Measured: Measured at BL week 16
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jul 2014 (estimated)
- Study start3 Sep 2014
- Primary completion6 Apr 2016
- Study completion6 Apr 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Chronic Heart FailureStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 225 participants (actual)
Sponsor and investigators
- Lead sponsor
- Adrian Hernandez
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Sponsor-investigator, Adrian Hernandez, Duke University
- Investigators
- Adrian Hernandez, MD,MHS,FAHA, Principal investigator, Duke University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02188784
- Sponsor's protocol ID
- Pro00054061
- Other IDs
- 2U10HL084904
- Acronym
- IRONOUT
- Status last verified
- Jun 2017
- First submitted
- 10 Jul 2014
- Last updated
- 11 Jul 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: After the study results have been published, site-specific participant data will be shared with sites upon request. Sites are expected to follow their specific institutional policies regarding sharing results with their participants.
Publications
Lewis GD, Malhotra R, Hernandez AF, McNulty SE, Smith A, Felker GM, Tang WHW, LaRue SJ, Redfield MM, Semigran MJ, Givertz MM, Van Buren P, Whellan D, Anstrom KJ, Shah MR, Desvigne-Nickens P, Butler J, Braunwald E; NHLBI Heart Failure Clinical Research Network. Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial. JAMA. 2017 May 16;317(19):1958-1966. doi: 10.1001/jama.2017.5427.
PubMed 28510680Lewis GD, Semigran MJ, Givertz MM, Malhotra R, Anstrom KJ, Hernandez AF, Shah MR, Braunwald E. Oral Iron Therapy for Heart Failure With Reduced Ejection Fraction: Design and Rationale for Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure. Circ Heart Fail. 2016 May;9(5):e000345. doi: 10.1161/CIRCHEARTFAILURE.115.000345.
PubMed 27140203
Study at a glance
From the registry record, last updated by the sponsor on 11 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Oral Iron Repletion Effects On Oxygen Uptake in Heart Failure
- ClinicalTrials.gov ID
- NCT02188784
- Acronym / sponsor ID
- IRONOUT / Pro00054061
- Conditions
- Chronic Heart Failure
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 225 participants (actual)
- Lead sponsor
- Adrian HernandezUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- 3 Sep 2014 (actual)
- Primary completion
- 6 Apr 2016 (actual)
- Study completion
- 6 Apr 2016 (actual)
- First posted
- 14 Jul 2014 (estimated)
- Results
- Posted 15 May 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to determine if oral iron (Fe) polysaccharide is superior to oral placebo in improving functional capacity as measured by change in peak VO2 (oxygen uptake) by CPET (Cardiopulmonary Exercise Testing) , of a broad population of patients with HFrEF (Heart Failure with Reduced Ejection Fraction) and Fe deficiency at 16 weeks.
Hypothesis: In a broad population of HFrEF patients with Fe deficiency, compared to oral placebo, therapy with oral Fe polysaccharide will be associated with improvement in functional capacity at 16 weeks as assessed by CPET.
Detailed description
Therapeutic options to further improve functional capacity and symptoms in HF beyond neurohormonal antagonism are limited. Studies have demonstrated impaired oxidative capacity of skeletal muscle among HF patients, which may contribute to symptoms of breathlessness and persistent fatigue.
In addition to its role in erythropoiesis, iron (Fe) plays a critical role in skeletal muscle's oxygen (O2)-storage capacity (myoglobin) and systemic aerobic energy production. As Fe deficiency is common in patients with symptomatic HF, repletion of iron stores may improve submaximal exercise capacity among these patients beyond the effects on erythropoiesis.
While intravenous Fe repletion in HF patients with mild Fe-deficiency (i.e. Ferritin <100 or Ferritin 100-299 with transferrin saturation <20%) with or without anemia global well-being and functional status, oral Fe repletion has not been studied. Furthermore, the efficacy of oral Fe to replete iron stores in a similar population and its impact on functional capacity, measured objectively by peak VO2, remains unknown.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Polysaccharide iron complex 150 mg | Active comparator | Drug: Polysaccharide Iron Complex 150 mgoral Fe polysaccharide 150mg twice daily for 16 weeks |
| Placebo (for Polysaccharide Iron Complex 150 mg) | Placebo comparator | Drug: Placebo (for Polysaccharide Iron Complex)Oral placebo twice a day for 16 weeks |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Age >18 years
- Previous clinical diagnosis of heart failure with current New York Heart Association (NYHA) Class II-IV symptoms LVEF≤0.40 within 2 years prior to consent, and ≥3 months after a major change in cardiac status (i.e. CABG or CRT).
- Serum ferritin between 15-100 ng/ml or serum ferritin between 100-299 ng/ml with transferrin saturation <20%
- Hemoglobin 9.0-13.5 g/dL (males), 9-13.5 (females) at time of enrollment
- Stable evidence-based medical therapy for HF (including beta-blocker and ACE-inhibitor/ARB unless previously deemed intolerant, and diuretics as necessary) with </= 100% change in dose for 30 days prior to randomization
Key exclusion criteria (15 listed)
- Presence of a neuromuscular, orthopedic or other non-cardiac condition that prevents the patient from exercise testing on a bicycle/treadmill ergometer and/or inability to achieve an RER ≥ 1.0 on screening/baseline CPET
- Severe renal dysfunction (eGFR< 20 ml/min/1.73m2)
- Severe liver disease (ALT or AST > 3x normal, alkaline phosphatase or bilirubin >2x normal)
- Gastrointestinal conditions known to impair Fe absorption (i.e. inflammatory bowel disease)
- Known active infection as defined by current use of oral or intravenous antimicrobial agents
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Polysaccharide Iron Complex 150 mgAlso: Feramax 150 mgOral Iron | Drug | Polysaccharide iron complex 150 mg |
| Placebo (for Polysaccharide Iron Complex)Sugar capsule designed to mimic Polysaccharide Iron Complex. | Drug | Placebo (for Polysaccharide Iron Complex 150 mg) |
Primary outcome
Change in Peak VO2 (ml/Min) (VO2 =Oxygen Consumption)
Time frame: Baseline (BL) and Week 16
To determine if oral Fe (Iron) polysaccharide is superior to oral placebo in improving functional capacity as measured by change in peak VO2 by CPET (Cardiopulmonary Exercise Testing) , of a broad population of patients with HFrEF (Heart Failure with Reduced Ejection Fraction) and Fe deficiency at 16 weeks.
5 secondary outcomes
Change From Baseline in Sub-maximal Exercise Capacity as Assessed by the 6 Minute Walk Test (6MWT)
Time frame: Measured at BL, week 8 and week 16
Change in Plasma NT-pro BNP
Time frame: Measured at Baseline and Week 16
Change in Health Status: Kansas City Cardiomyopathy Questionnaire (KCCQ) - Clinical Summary Score
Time frame: Measured at Baseline, Week 8 and Week 16
Change From Baseline in O2 Uptake Kinetics as Assessed by Mean Response Time From CPET
Time frame: Measured at BL week 16
Change From Baseline in Ventilatory Efficiency Defined by Ve/VCO2
Time frame: Measured at BL week 16
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jul 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 28510680Lewis GD, Malhotra R, Hernandez AF, McNulty SE, Smith A, Felker GM, Tang WHW, LaRue SJ, Redfield MM, Semigran MJ, Givertz MM, Van Buren P, Whellan D, Anstrom KJ, Shah MR, Desvigne-Nickens P, Butler J, Braunwald E; NHLBI Heart Failure Clinical Research Network. Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial. JAMA. 2017 May 16;317(19):1958-1966. doi: 10.1001/jama.2017.5427.
- Derived from this study: PubMed 27140203Lewis GD, Semigran MJ, Givertz MM, Malhotra R, Anstrom KJ, Hernandez AF, Shah MR, Braunwald E. Oral Iron Therapy for Heart Failure With Reduced Ejection Fraction: Design and Rationale for Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure. Circ Heart Fail. 2016 May;9(5):e000345. doi: 10.1161/CIRCHEARTFAILURE.115.000345.
- Individual participant dataSharing planned: Yes. After the study results have been published, site-specific participant data will be shared with sites upon request. Sites are expected to follow their specific institutional policies regarding sharing results with their participants.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Adrian Hernandez, MD,MHS,FAHA principal investigator
Duke University
17 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Polysaccharide Iron Complex 150 mg in people with Chronic Heart Failure, run by Adrian Hernandez at 17 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 17 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 May 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Peak VO2 (ml/Min) (VO2 =Oxygen Consumption) (time frame: Baseline (BL) and Week 16). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02188784, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jul 2017.